Lengthening the Guanidine–Aryl Linker of Phenylpyrimidinylguanidines Increases Their Potency as Inhibitors of FOXO3-Induced Gene Transcription

0562268 - FGÚ 2023 RIV US eng J - Journal Article
Kohoutová, Klára - Dočekal, V. - Ausserlechner, M. J. - Kaiser, N. - Tekel, A. - Mandal, R. - Horváth, M. - Obšilová, Veronika - Veselý, J. - Hagenbuchner, J. - Obšil, Tomáš
Lengthening the Guanidine–Aryl Linker of Phenylpyrimidinylguanidines Increases Their Potency as Inhibitors of FOXO3-Induced Gene Transcription.
ACS Omega. Roč. 7, č. 38 (2022), s. 34632-34646. ISSN 2470-1343. E-ISSN 2470-1343
R&D Projects: GA ČR(CZ) GA21-02080S
Institutional support: RVO:67985823
Keywords : DNA binding * forkhead box O 3 * nuclear magnetic resonance * neuroblastoma * chemoresistance * senescence
OECD category: Biochemistry and molecular biology
Impact factor: 4.1, year: 2022
Method of publishing: Open access
https://doi.org/10.1021/acsomega.2c04613

Increased FOXO3 nuclear localization is involved in neuroblastoma chemoresistance and tumor angiogenesis. Accordingly, FOXO3 inhibition is a promising strategy for boosting antitumor immune responses and suppressing FOXO3-mediated therapy resistance in cancer cells. However, no FOXO3 inhibitors are currently available for clinical use. Nevertheless, we have recently identified (4-propoxy)phenylpyrimidinylguanidine as a FOXO3 inhibitor in cancer cells in the low micromolar range. Here, we report the synthesis and structure–activity relationship study of a small library of its derivatives, some of which inhibit FOXO3-induced gene transcription in cancer cells in a submicromolar range and are thus 1 order of magnitude more potent than their parent compound. By NMR and molecular docking, we showed that these compounds differ in their interactions with the DNA-binding domain of FOXO3. These results may provide a foundation for further optimizing (4-propoxy)phenylpyrimidinylguanidine and developing therapeutics for inhibiting the activity of forkhead box (FOX) transcription factors and their interactions with other binding partners.
Permanent Link: https://hdl.handle.net/11104/0334626